Example of the tDMR finder algorithm used for the HOXD3 gene. Tissue-specific differentially methylated regions were identified in a two-step approach: first, we identified tDMPs. CpGs were considered to be tDMPs when there was a genome-wide significant mean difference of ≥ 10%. The mean difference was expressed as a mean sum of squares. A difference ≥ 10% equals a mean sum of squares ≥ 0.01 (square of 10% = 0.12). To test whether the difference was significant, we applied a linear model per CpG site, with a random effect for each individual to correct for any inter-individual variation. From this linear model we obtained a P value (F-test) per CpG site and used a multiple testing corrected P value as a cut-off (10-7). Second, we identified tDMRs as regions with at least three tDMPs with an inter-CpG distance of at most 1 kb and a maximum of three non-tDMPs. Mb, megabase; tDMP, tissue-specific differentially methylated position; tDMR, tissue-specific differentially methylated region.